Tài liệu Báo cáo khoa học: Neuronal growth-inhibitory factor (metallothionein-3): reactivity and

MINIREVIEW

Neuronal growth-inhibitory factor (metallothionein-3):

reactivity and structure of metal–thiolate clusters*

Peter Faller1,2

1 CNRS, LCC (Laboratoire de Chimie de Coordination), Toulouse, France

2 Universite´ de Toulouse, UPS, INPT; LCC; Toulouse, France

Introduction

Metallothionin-3 (MT3) was originally dubbed neuro￾nal growth-inhibitory factor (GIF) [1] because of the

discovery that it is a factor in brain extract with the

ability to inhibit neuronal outgrowth. Moreover, MT3

or GIF was reported to be down-regulated in extract

from Alzheimer’s disease (AD) brain. Later on it

became clear that GIF belongs to the metallothionein

(MT) family based on its high cysteine and metal con￾tents. In mammals, the MT family consists of four dif￾ferent subfamilies designated MT1 to MT4 [2–4].

Mammalian MTs are composed of a single polypep￾tide chain of 61–68 residues. They are characterized by

a conserved array of 20 cysteines and the absence of

His and aromatic amino acids. MT3 contains 68

amino acids with 70% sequence identity to the MT1

and MT2 (MT1 ⁄ 2) isoforms. The MT3 sequence

contains two inserts: an acidic hexapeptide in the C￾terminal region and a Thr in position 5. Moreover, a

conserved Cys-Pro-Cys-Pro motif between positions 6

and 9 is unique to MT3 [1,4,5].

All mammalian MTs can bind a variety of different

mono-, di- and trivalent metal ions via their cysteine

residues. Most relevant under normal conditions in

biology is the binding of Zn2+ and Cu+. However,

MTs can also bind other metals (Cd2+, Hg2+, Ag+,

Pt2+, Pb2+ and Bi3+) when they are administered to

animals. Classically, the metal ions studied in detail

[mainly Zn(II), Cu(I), Cd(II), Hg(II) and Ag(I)] are

Keywords

bioinorganic chemistry; copper; growth

inhibitory factor; metallothionein; metal–

thiolate clusters; protein structure; zinc

Correspondence

P. Faller, CNRS, LCC 205, route de

Narbonne, 31077 Toulouse, France

Fax: +33 5 61 55 30 03

Tel: +33 5 61 33 31 62

E-mail: [email protected]

*This article is dedicated to Prof. M. Vasak

on the occasion of his retirement

(Received 3 December 2009, revised 4 May

2010, accepted 17 May 2010)

doi:10.1111/j.1742-4658.2010.07717.x

Metallothionein-3, also called neuronal growth-inhibitory factor, is one of

the four members of the mammalian metallothionein family, which in turn

belongs to the metallothionein, a class of ubiquitously occurring low￾molecular-weight cysteine- and metal-rich proteins containing metal–

thiolate clusters. Mammalian metallothioneins contain two metal–thiolate

clusters of the type M(II)3-Cys9 and M(II)4-Cys11 [or Cu(I)4-CysS6-9].

Although metallothionein-3 shares these metal clusters with the well￾characterized metallothionein-1 and metallothionein-2, it shows distinct bio￾logical, structural and chemical properties. This short review focuses on the

recent developments regarding the chemistry of the metal clusters in metal￾lothionein-3, in comparison to those in metallothionein-1 and metallothion￾ein-2, and discusses the possible biological and functional implications.

Abbreviations

Ab, b-amyloid; AD, Alzheimer’s disease; apo-T, apo-thionein; DTNB, 5,5¢-dithiobis(2-nitrobenzoic acid)); GIF, neuronal growth-inhibitory factor;

M(II), divalent metal ion; MT, metallothionein.

FEBS Journal 277 (2010) 2921–2930 Journal compilation ª 2010 FEBS. No claim to original French government works 2921